Relationship of the Magnitude of Member Cost-Share and Medication Persistence With Newly Initiated Renin Angiotensin System Blockers

BACKGROUND: Effective treatment for chronic diseases often requires medication refill persistence. Health plans have frequently increased the amount of member cost-sharing by implementing tier-copayment pharmacy benefit designs and raising copayments. However, increased member cost share may present a barrier to the management of chronic conditions. Little is known about the relationship between the magnitude of member cost-sharing and antihypertensive persistence among members newly initiating therapy. OBJECTIVES: To investigate and quantify the relationship between amount of prescription cost-sharing and medication refill persistence among members newly initiating therapy with a single-agent angiotensin system blocker—either an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). METHODS: This was an observational cohort study of pharmacy and medical claims data for 29 employers with approximately 310,000 beneficiaries that did not have a change in pharmacy benefits including the amount of member cost-share in 2004. The claims data were supplemented with census data for household income and race at the Zip Code level. Selected patients were new users of single-agent ACEIs or ARBs (i.e., excluding ACEI or ARB in combination with hydrochlorothiazide or amlopdipine) between January 1 and June30, 2004, without a pharmacy claim for an ACEI or an ARB in the 6 months prior to the index claim for either drug type. Medication refill persistence was measured in 3 ways: (1) total number of days without ACEIs or ARBs during6 months follow-up, (2) proportion of days covered (PDC) with less than 80% defined as nonpersistent during 6 months follow-up, and (3) number of days to the first gap of more than 30 days in medication coverage from the index date to end of 2004 (mean [SD] follow-up=9.2 [1.8] months). Three statistical models were fit: Tobit model, examining the association between cost-sharing and total number of medication gap days; logistic regression, testing the association between cost-sharing and odds of being non-persistent; and Cox proportional hazards model, assessing the association between cost-sharing and time to a 30-day gap. RESULTS: Among the eligible population, a study cohort of 1,351 members newly initiating a single-agent ACEI or ARB was identified. These members were 41.8% female and had a mean age of 55.9 (SD=13.1) years. On average,their member cost-share was $12.42 (SD=$8.50) per 30-day supply. Each$1 increment in per 30-day cost-share was associated with a 1.9% increase in total gap (β=0.019, 95% confidence interval [CI], 0.007-0.030, P=0.001), a2.8% increase in the odds of being nonpersistent (odds ratio [OR]=1.028, 95%CI,1.011-1.045, P=0.001), and a 1.0% increase in the risk of having a gap of more than 30 days (hazard ratio [HR]=1.010, 95% CI, 1.001-1.019, P=0.034).Following transformation of the cost-sharing coefficient in each model, a $10increment in cost-share had a consistent negative influence; 18.9% greater total gap days (β=0.189, 95% CI, 0.073-0.304), 31.9% greater odds of being nonpersistent (OR=1.319, 95% CI, 1.120-1.553), and 10.2% larger hazard of having a gap of more than 30 days (HR=1.102, 95% CI, 1.007-1.205). CONCLUSIONS: For members newly initiating single-agent angiotensin system blocking medication, the amount of prescription cost-sharing was associated with a negative impact on refill persistence.

O utpatient prescription drug spending in the United States was $200.7 billion in 2005 with a 5.8% increase over 2004. 1 To control rising prescription drug costs, managed care organizations (MCOs) and the employers with whom they contract began utilizing multitiered formularies after the early 1990s. 2 To offset the continued increase in prescription drug spending, many health plans have increased prescription cost-sharing across all copayment tiers. 2 In 2006, the most common commercial pharmacy benefit design employed 3-tier copayments with average member cost-share of $11 for BACKGROUND: Effective treatment for chronic diseases often requires medication refill persistence.Health plans have frequently increased the amount of member cost-sharing by implementing tier-copayment pharmacy benefit designs and raising copayments. However,increased member costsharemay present abarrier to the management of chronic conditions. Little is known about the relationship between the magnitude of member cost-sharing and antihypertensive persistence among members newly initiating therapy.
OBJECTIVE: To investigate and quantify the relationship between amount of prescription cost-sharing and medication refill persistence among members newly initiating therapywith asingle-agent angiotensin system blockereither an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker(ARB).
METHODS: This wasanobservational cohort studyofpharmacyand medical claims data for 29 employers with approximately 310,000 beneficiaries that did not have achange in pharmacybenefits including the amount of member cost-sharein2004. The claims data weresupplemented with census data for household income and race at the Zip Code level. Selected patients werenew users of single-agent ACEIs or ARBs (i.e., excluding ACEI or ARB in combination with hydrochlorothiazide or amlopdipine) between January1an dJune 30,2004, without apharmacyclaim for an ACEI or an ARB in the 6months prior to the indexclaim for either drug type.Medication refill persistence was measured in 3ways: (1) total number of days without ACEIs or ARBs during 6months follow-up, (2) proportion of days covered (PDC) with less than 80% defined as nonpersistent during 6months follow-up,and (3) number of days to the first gap of morethan 30 days in medication coverage from the index date to end of 2004 (mean [SD] follow-up =9.2 [1.8] months). Three statistical models werefit: Tobit model, examining the association between cost-sharing and total number of medication gap days; logistic regression, testing the association between cost-sharing and odds of being nonpersistent; and Cox proportional hazards model, assessing the association between cost-sharing and time to a30-day gap.
CONCLUSION: For members newly initiating single-agent angiotensin system blocking medication, the amount of prescription cost-sharing wasassociated with anegative impact on refill persistence.

Relationship of the Magnitude of Member Cost-Share and Medication Persistence With Newly Initiated Renin Angiotensin System Blockers
Relationship of the Magnitude of Member Cost-Share and Medication Persistence with Newly Initiated Renin Angiotensin System Blockers generic drugs, $24 for preferred brand-name drugs, and $38 for nonpreferred brand-name drugs. 3 One rationale behind prescription cost-sharing is to make consumers sensitive to prescription costs so that they will limit "nonessential" use and utilize generic or less expensive branded drugs when needed. In ar ecent literatures ummaryo f6 5 studies, researchers examined prescription drug cost-sharing associations with medication and medical utilization and spending. 4 Using an unspecified meta-analytic calculation methodology,t he authors found that for each 10% increase in cost-sharing, prescription drug spending decreased by 2% to 6%, dependent upon the drug class and the patient conditions. In as tatistical model derived from ac ross-sectional analysis of claims data from 25 employers, it was estimated that doubling a member' sc opayment was associated with a2 2% to 35% reduction in average annual prescription drug spending per member,w ith ap roportional reduction in utilization. 5 Other well-designed studies assessing pharmaceutical utilization and spending associated with changes to the pharmacy benefit design, as defined by Goldman et al., demonstrated similar trends in decreased utilization and costs associated with increased cost-share. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] However,i ns everal of the better designed (e.g., pre-post with comparison group) studies evaluating the effect of benefit design changes, which result in higher cost-sharet os ome members, researchers found much smaller decreases in utilization than observed in the cross-sectional studies. These authors also found significant shifts from nonpreferred products to preferred products, one of the desired outcomes of multitier pharmacy benefit designs. [14][15][20][21][22] A pre-post comparison of utilization of diabetes medication suggested that ag reater than $10 increase in cost-sharei s necessarytoinduce asignificant decrease in utilization. 11 An unintended consequence of large increases in cost-sharing with subsequent large reductions in prescription drug spending may be that members forgo "essential" medication use, raising concernabout adverse health outcomes, particularly for individuals with chronic illness. 9 In aw ell-designed pre-post with comparison group study,the authors found no significant differences in medical utilization, including inpatient hospital admissions, emergency room visits, and office visits, following implementation of ac opayment increase. [21][22] That study also found that rates of persistency with antihypertensive and antilipidemic therapy weren ot significantly affected by the copayment change. The minimal association between medical outcomes and pharmacy cost-shareinthat study may in part be due to the small increases in cost-sharing most members experienced; cost-sharing went from a2-tier structureof$7and $12 to a3-tier of $8, $15, and $25. Based on pre-implementation claims, only 14% of overall utilization, 29% of antihypertensive utilization, and 11% of antilipidemic utilization weres ubject to the largest increase in cost-sharef rom$ 12 to $25. All other members' cost-sharing went from either $7 to $8 or from $12 to $15.
In addition, an assessment of aC anadian provincial health system change in prescription coverage from $2 copayment per prescription to 25% coinsurance with income-based out-ofpocket annual maximums showed no dramatic differences in persistence or in cardiovascular outcomes in apre-post design. 24 This Canadian study is limited because it is not possible to quantify the individual difference in cost-shareper prescription, and the U.S. health system lacks acomparable type of benefit design with income-based annual out-of-pocket maximum cost-share.
It is important to develop an understanding of the incremental effect that member cost-sharing has on "essential" medication persistence, especially for members newly initiating medication therapy.A mong cardiovascular medications shown to reduce medical events, such as antihypertensives and lipid-lowering therapy,ahandful of researchers have examined the association between prescription cost-sharing and medication persistence, but without consistent results. [6][7][8][9]14,17,20,[23][24][25][26][27] These studies have consisted of am ix of users newly initiating and those currently on therapy.A nother limitation of these studies is inconsistency in the definition of persistence and persistence measurement methodology. 28 Therefore, it is difficult to make comparisons between studies.
Persistence is generally measured in 3ways, as afunction of: (1) medication possession ratio (MPR) or proportion of days covered (PDC); (2) medication availability at afixed time point; or (3) gaps in medication coverage. 29 Even though quasi-experimental study design (pre-post with comparison group) has good internal validity,itcan only examine whether thereisanimpact of prescription cost-sharing on persistence based on the magnitude of cost-sharing change. The fixed cost-sharing in pre-post comparison studies does not allow assessment of ac ontinuous quantitative relationship between cost-sharea nd persistence. Furthermore, in pre-post comparison studies, not only the effects of prescription cost-sharing, but also the responses towardap harmacy benefits change, arem easured. In most cross-sectional studies, cost-sharing is either assessed by aprice index or approximated by formularyt iers, neither of which measures members' actual economic burden. To our knowledge, at the time of this research, no one had investigated members newly initiated on therapy and the associated proportional effect of prescription cost-sharing on the level of nonpersistence. Finally,t he main purpose of most of the published studies was to quantify the impact of ac hange in cost-sharing on prescription drug utilization, expenditure, and persistence. [8][9]14,17,20,24 To our knowledge, the studies of cardiovascular drugs in which authors have attempted to quantify mathematically the relationship between cost-sharea nd persistence werei nt he statin drug class 6,7,25 or focused on congestive heart failure patients. 23 Tw oantihypertensive studies evaluating the relationship between persistence and member cost-sharef ocused on differences in persistence between 3c opayment tiers using the PDC metric. 26,27 Both of the antihypertensive studies found that higher cost-sharewas asignificant independent negative predictor of persistence. However,t he studies arel imited due to the use of 1p ersistence measurea nd the inability to quantify the relationship between the amount of cost-shareand persistence.
The objective in this study was to investigate and quantify the influence of the amount of prescription cost-shareo n medication refill persistence among members newly initiating angiotensin system-blockers: angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). ACEIs and ARBs arep rimarily prescribed for hypertension 30 and have been associated with higher persistence rates than other antihypertensive therapeutic classes. [31][32][33] They have a similar mechanism of action, reducing the effect of angiotensin II on the body,a nd nearly identical side effect profiles with ah igher proportion of patients reporting cough with ACEIs. [34][35] The equivalent effectiveness and safety of ACEIs and ARBs has been recently reported in the Agency for Health Research and Quality document "Comparative effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists (ARBs) for treating hypertension." 35 During the present study,6s ingle-agent ACEIs were available by generic name (captopril, enalapril, fosinopril, lisinopril, moexipril, and benazepril), 4single-agent ACEIs were available as brand only (trandolapril, perindopril, quinapril, and ramipril), and all single-agent ARBs wereavailable as brand only. This distribution of study drugs across copayment tiers permits analysis of the relationship between cost-sharea mount and persistence.

nn METHODS
This observational cohort study used aM idwest commercial insurer' sm edical and pharmacy administrative claims data for health benefit services provided to 1.7 million members. To be eligible for analysis, members werer equired to have been continuously enrolled from July 1, 2003 to December 31, 2004 with ahealth plan group, pharmacy benefit, and cost-sharethat did not change during 2004. Therewere29employers that met these criteria, representing approximately 10% of the total membership of this commercial insurer.F romt hese 29 employers, we identified new users of single angiotensin systemblocking (ACEI or ARB) agents. Combination products were excluded because the single angiotensin system-blocking agents area ssociated with significantly higher persistence rates than other antihypertensive drug classes. 36 By limiting the analysis to single-agent angiotensin system blockers, we reduce the potential for agents such as hydrochlorothiazide in combination products to negatively influence persistence. An ew user was defined as an individual who started treatment with ACEI (Medi-Span' s6 -digit Generic Product Identifier [GPI] code 361000) or ARB (code 361500) single agents (excluding ACEI/ calcium channel blockers, ACEI/hydrochlorothiazide, and ARB/ hydrochlorothiazide combinations) between January1 ,2 004 and June 30,2004 with no ACEI or ARB single agents or combinations dispensed in the 6m onths (180 days) preceding the index date.
The first pharmacy claim for an ACEI or ARB single agent was defined as the index event, and the date of the index pharmacy claim was defined as the index date. The new users had to meet several inclusion criteria: (1) 18 years of age or older on the index date, (2) at least 28 days supply in the index pharmacy claim, (3) no facility hospitalization or long-term carec laim of any duration after the index date, and (4) no diagnosis of dementia (ICD-9-CM codes 290.xx, 294.1x, 331.0x, 331.1x or 331.2x). Members weref ollowed for 2p eriods: from the index date to 6months after the index date and from the index date to the end of 2004.

Variables
Medication refill persistence was measured 3w ays based on days supply recorded in pharmacy claims to quantify the intensity and duration: 28,29 (1) total gap or total number of days without medication during the first 6m onths of treatment, (2) proportion of days covered (PDC) with less than 80% defined as nonpersistent (less than 144 days of coverage) during the first 6months of treatment, and (3) time to agap of morethan 30 days in medication coverage from the index date to the end of 2004. Days supply that overlapped with previous pharmacy claims or extended past the observation period werenot used in calculating persistence. Switching to asingle-agent ARB or ACEI was counted as acontinuation of treatment as long as the other criteria for continuation (e.g., no morethan a30-day gap) were met. However,members switching to acombination product or to an antihypertensive product in adifferent therapy class (e.g., beta blockers, calcium channel blockers) weredefined as having terminated therapy on the date that the switch claim was filled. Members' out-of-pocket payment for the index prescription as recorded in pharmacy claims was used to measurecost-sharing after adjusting to a3 0d ays supply (cost-sharing for the initial claim was divided by days supply to yield cost-sharing per day, then multiplied by 30).
Control variables weres elected according to Andersen' s behavioral model of health services use 37 and previous empirical studies. [6][7]23,25,[31][32][33]36,[38][39][40][41] Andersen' sm odel was originally developed in the late 1960s to explain how and why families use health services. This model has since been adapted to predict and explain prescription drug use. [42][43][44] According to the model, use of health services, including prescription drugs, is af unction of patients' predisposing characteristics, enabling resources, and need factors. In this study,p redisposing characteristics are those variables that describe the predisposition of individuals to continuously use an angiotensin system blocker; enabling resourcesdescribetheabilityofpatientstocontinuouslyobtainand use an angiotensin system blocker; and need factors describe the professionally determined requirements for continuous use of Relationship of the Magnitude of Member Cost-Share and Medication Persistence with Newly Initiated Renin Angiotensin System Blockers an angiotensin system blocker.
Predisposing characteristics included age, gender,r ace, and whether am ember previously used any antihypertensive medications other than ACEIs and ARBs. Because race is not available in claims data, it was controlled on an aggregate level using percentage of people who reported their race as white only in am ember' sZ ip Code area based on the Census 2000 data. 45 Other antihypertensives included diuretics (General Product Indentifier Code beginning 37), beta-blockers (33), calcium channel blockers (34), antiadrenergic antihypertensives (3620), aldosterone receptor blockers (3625), direct vasodilators (364000), and antihypertensive combinations (3699) without ACEIs and ARBs.
Enabling resources included residence (urban, rural, or super rural); income; number of unique medications in prior 6 months; number of doctor visits from July 1, 2003 to the end of 2004; initial therapeutic class (ACEIs or ARBs); utilization of mail-order service at any time during follow-up; presence of a yearly out-of-pocket maximum in member' spharmacy benefits; and whether am ember used any antidepressant medications: mirtazapine (GPI code 580300), trazodone (58120080), monoamine oxidase inhibitors (581000), selective serotonin reuptake inhibitors (SSRIs, 581600), serotonin norepinephrine reuptake inhibitors (SNRIs, 581800), tricyclic agents (582000), and miscellaneous antidepressants (583000) in the prior 6 months. Tr icyclic agents weren ot coded as antidepressant medications in those members with ad iagnosis of diabetes as these drugs areoften used for diabetic neuropathy.
Zip Codes wereu sed to classify members as living in an urban, rural, or super rural area according to the Medicare ambulance fee schedule of the Center for Medicarea nd Medicaid Services (CMS). 46 Ar ural area is defined as an area outside aMetropolitan Statistical Area (MSA) or aNew England County Metropolitan Area, or an area within an MSA identified as rural using the Goldsmith modification. 47 Asuper rural area is defined as ar ural area determined by the Secretaryo fH ousing and Urban Development to be in the lowest 25th percentile of all rural population arrayed by population density. 48 An area that is not classified as arural or super rural area is considered an urban area. Income was also controlled on an aggregate level using household median income in am ember' sZ ip Code area based on the Census 2000 Data. 45 Need factors controlled for included conditions that angiotensin system blocking medications areg enerally used to treat or conditions associated with treatment. These conditions were based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis and procedurecodes recorded in medical claims between July 1, 2003 and December 31,2004

Statistical Analysis
Statistical analyses wereconducted using SAS 9.1 (SAS Institute Inc., Cary, NC). Results wereconsidered statistically significant at P <0.05 (2-tailed). Descriptive statistics, numbers, and percentages for categorical variables and means and standard deviations for continuous variables werec alculated. These descriptive results werea lso stratified by cost-sharing tertiles. Cost-sharing tertiles wereconstructed according to the frequency distribution of cost-sharing, with each containing about one thirdo ft he study members. Comparisons of control variables across cost-sharing tertiles werec onducted with chi-squaretests for categorical variables and analyses of variance (ANOVA) for continuous variables. Three statistical models corresponding to the 3measures of medication refill persistence werep erformed: Tobit model (proc lifereg), logistic regression (proc logistic) and Cox proportional hazards model (proc phreg). All of these models adjusted for the same set of control variables.
The Tobit model was used to model the association between cost-sharing and total gap over the first 6months of treatment. This approach is appropriate for ad ependent variable with a distribution that is spread out over al arge range of positive values but with al arge proportion of observations at the value zero. In this study,total gap has such adistribution. Although a linear model could capturet he expected value of such a dependent variable, al inear model will likely lead to negative predictions for some subjects. In the Tobit model, an atural logarithmic transformation of total gap is used to address the skewness in the distribution of total gap. Because the natural logarithm of zeroi sn ot defined, everyp atient' st otal gap is added by one. Normal distribution after log transformation is a critical assumption under the Tobit model. This assumption was examined using histogram of residuals (i.e., predicted total gap minus actual total gap). In this study,the histogram of residuals shows that the normal distribution assumption under the Tobit model is met (data not shown).
Logistic regression, which is appropriate for describing the relationship between ac ategorical dependent variable and a set of predictors, was used to examine the association between cost-sharing and being nonpersistent (PDC <80%) during the first 6months of treatment. The overall fit of the logistic model was assessed using the Hosmer-Lemeshow test. This test divides subjects into deciles based on predicted probabilities, then computes ac hi-squaref romo bserved and expected frequencies. When the test is not significant ( P value ≥ 0.05), the null hypothesis that the model fits the data well cannot be rejected. The logistic regression model in this study has aH osmer-Lemeshow goodness-of-fit test P value of 0.10 suggesting that the model fits the data ( χ 2 [8] =13. 27).
Cox proportional hazards model with the Breslow method for ties was used to test the association between cost-sharing and time to ag ap of moret han 30 days from the index date to the end of 2004. The Cox proportional hazards model assesses the effects of different covariates on logarithm of rate (log[rate]), without assuming ac onstant rate over time. Ac rucial assumption of the Cox proportional hazards model is proportional hazards (i.e., the hazardofhaving an event at any given time for an individual in one group is proportional to the hazardatthat time for as imilar individual in the other group.) This assumption was examined by plotting the log-cumulative hazardf unctions against the log(t ). For this study,t he plot of log-cumulative hazardfunctions against the log(t )suggests that the proportional hazards assumption was satisfied (data not shown). Survival curves stratified by cost-sharing tertiles were shown after adjusting for all the control variables in the Cox proportional hazards model.

Patient Privacy
Alimited data set was received after direct individual identifiers wereremoved to meet the requirements of the Health Insurance Portability and Accountability Act (HIPAA). Year of birth and Zip Codes areallowed in limited data sets. This study was approved by the University of Minnesota' sInstitutional Review Board.  Table 1s hows the members' pharmacy benefits designs. A majority of the members had amultitier formularywith 52.9% in a2-tier copayment structureand 42.6% in a3-tier structure. The use of ac oinsurance-only pharmacy-benefits design was rare(0.4% of members) in this study cohort.
As shown in  (Table 2). Members who paid the highest cost-sharing amount for their initial claim werem orel ikely to start with ARBs than members who paid lower cost-sharing amounts. This is expected because all ARBs wereb rand drugs and had higher cost-share than ACEIs, which werem ostly available as generics. In addition, members who wereinthe thirdcost-sharing tertile (highest cost-sharing amount) lived in aZip Code with lower household median income, had fewer doctor visits, and wereless likely to have ay early out-of-pocket maximum in their pharmacy benefits design compared with the members in the other 2 tertiles. The second cost-sharing tertile had significantly fewer members who used mail-order pharmacies and morem embers who had ad iagnosis of essential hypertension compared with the first and thirdtertiles. These differences wereadjusted in our multivariate analyses.
During the first 6months of treatment, the study members, on average, had 53 (SD=52) days (range =0-152) without an angiotensin system blocking agent. During the first 6m onths, 8% of these members had no gap and 47% werec lassified as being nonpersistent (PDC <80%). From the index date to the end of 2004, 54% of these members had agap of morethan 30 days with an average time to the gap of 172 (SD=108) days. Table 3shows the results from the Tobit model. After controlling for members' other characteristics, the coefficient of costsharing was 0.019 (95% confidence interval [CI], 0.007-0.030, P =0.001). Interpreting the coefficients in aT obit model can be challenging because the marginal impact of X on Y is nonlinear. The approach is to take the Tobit estimate and multiply it by a factor to obtain the marginal impact. The factor is the standard normal cumulative distribution function at the sample mean values of all the independent variables, which in our case was 0.98 (almost 1). Therefore, the Tobit model suggests that starting at the mean values of all the independent variables including cost-sharing, a$ 1i ncrease in cost-sharing was associated with an approximate 1.9% increase in total gap. Following transformation of the cost-sharing coefficient, a$ 10 greater cost-share was associated with an approximate 18.9% increase in total gap (95% CI, 7.3%-30.4%).

Results of the Tobit Model
Besides cost-sharing, 6o ther significant independent predictors werei dentified. A1 -year increase in age was associated with an approximate 1.2% decrease in total gap. Residing in Zip Code areas with ah igher prevalence of white residents, using mail-order service, having an out-of-pocket annual maximum on prescription drug spending, and having diagnoses of dyslipidemia and myocardial infarction werea lso associated with alower total gap. Specifically,a1%increase in the proportion of white people in the member' sZ ip Code was associated with a1 .1% decrease in total gap; members who used mailorder service had a8 6.4% lower total gap than those who did not use mail-order service; members who had an out-of-pocket annual maximum on prescription drug spending had a2 9.7% lower total gap than those who did not have this benefit; and members who wered iagnosed with dyslipidemia and myocardial infarction had a20.5% and 47.5% lower total gap compared with those who did not have these diagnoses, respectively.   In addition to cost-sharing, 3c ontrol variables werea lso significant in predicting the odds of being nonpersistent. A 1-year increase in age was associated with a2.0% decrease in the odds of being nonpersistent. A1%increase in the proportion of Caucasians in the member' sZip Code was associated with a1.4% decrease in the odds of being nonpersistent. Members who used mail-order service had a43.0% lower odds of being nonpersistent compared to those who did not use mail-order service. Consistent with the Tobit model and logistic regression, age, residing in Zip Code census areas with ah igher prevalence of white residents, and using mail-order service werea lso significant predictors of the risk of having agap of morethan 30 days in the coverage of ACEIs or ARBs. A1-year increase in age was associated with a1 .1% decrease in the risk of having ag ap of moret han 30 days. A1 %i ncrease in the proportion of white residents in the member' sZip Code was associated with a 0.8% decrease in the risk of having a30day gap. Members who used mail-order service had a22.0% lower risk of having agap of greater than 30 days than those who did not use mail-order service.

Results of the Cox Proportional Hazards Model
Figure2s hows the estimated survival curves after adjusting for all control variables at the mean values in the Cox proportional hazards model. The survival curves weres tratified by cost-sharing tertiles. The survivor function decreases over time and mored ramatically in the higher cost-sharing tertile. After up to 1year of follow-up, 10% moremembers in the lowest cost-sharing tertile ($0.00-$8.30) weres till persistent (i.e., not having a3 0d ay gap yet) compared with those in the highest cost-sharing tertile ($13.01-$127.98).

nn DISCUSSION
Angiotensin system-blocking medication refill persistence intensity and duration among members newly initiating therapy werec onsistently found to be independently associated with cost-share. In addition, the relationship between medication persistence and cost-share, quantified as $1 greater cost-share, was associated with a1 .9% larger medication gap during the first 6m onths of treatment. To our knowledge, these findings aret he first to quantify the relationship between persistence and the amount of member cost-sharef or patients newly initiating angiotensin system-blocking medication. Previously published studies focusing on pharmacy benefit design cost-sharing changes have shown minimal impact on antihypertensive persistence among current utilizers. These studies aren ot comparable to the present study because the subjects werec urrent users and because the effect of a fixed benefit design change was being tested. In our crosssectional study,members werenewly initiating therapy and had variable per 30 day cost-shareamounts ranging from $0 to $128  Relationship of the Magnitude of Member Cost-Share and Medication Persistence with Newly Initiated Renin Angiotensin System Blockers allowing us to quantify the associated relationship between cost shareand persistence.
The results of this study arec omparable to the findings of other persistence studies employing ac ross-sectional study design. Among ac ombination of members currently utilizing and newly initiating statin therapy,Ellis et al. showed that higher member cost-sharing amounts werea ssociated with large decreases in statin persistence rates. 25 As compared with members who had acopayment of less than $10, members who paid at least $10 but less than $20 and those who paid $20 or greater had 30% and 211% greater odds of being nonpersistent (cumulative multiple refill interval gap [CMG]>20%), respectively.A3 0% greater odds of being nonpersistent when comparing ac ost-sharing of $10 per 30 days supply to $20 is similar to the finding in this study of a3 1.9% increase in the odds of being nonpersistent for am ean $12 versus $22 cost-sharing per 30 days supply.T aira et al. demonstrated that compliance with antihypertensive medications was significantly lower in higher than in lower copayment tiers. 27 As compared with members who used generics with ac opayment of $5, members who used preferred brand-name drugs with ac opayment of a$ 20 and those who used non-preferred brand-name drugs with acopayment of $20 to $165 had 24% and 52% less odds of being compliant, respectively.Thiebaud et al. found that higher cost-sharing was associated with lower statin utilization. 49 They reported that a$ 1i ncrease in brand drug and generic copay was associated with a0.9% and 1.6% decrease in month-ly days supply of brand drug and generics, respectively.T hese findings aresimilar to our finding that a$1increase in cost-sharing was associated with a1.9% increase in total gap.
We found that age, percentage of population self-reporting white only race in the patient' sareaofresidence, and use of mailorder service werestatistically significant predictors of total gap, being nonpersistent, and time to agap of >30 days in the 3models. Some empirical studies have shown that age and race were significant predictors of medication persistence. 31,36,38,[40][41] Benner et al., for example, reported that members of black and other nonwhite races werel ess persistent with statin therapy. 41 Although we also found as ignificant association between persistence and race, this finding should be interpreted cautiously.B ecause claims data do not include race at the individual level, we measured race at an aggregate level (i.e., percentage of population in the patient' sZ ip Code area selfreporting white as their only racial group).
In addition, results of this study suggest that members who fill prescriptions by mail-order pharmacies have greater persistence rates. However,t he impact of mail-order service may be artificial because the calculation of persistence in this study was based on days supply recorded in pharmacy claims. Mail-order pharmacies have larger days supply than community pharmacies. Within afi xed observation period, members who receive medications from mail-order pharmacies will have fewer refills than those who use community pharmacies and thereforet he former group will be less likely to have ag ap. We believe the impact of mail-order claims on our results is minimal because only 8.3% of all the claims and 18.0% of total days supply during the first 6m onths of treatment arem ail-order.I na ddition, mail-order was adjusted for in all 3m odels. In order to remove the possibility of the impact of mail-order service on the outcome, the 3models werer erun with restriction to members with community pharmacy claims only.The impact of cost-share on persistence did not change in all the 3m odels (data not shown).
We also found that having an out-of-pocket annual maximum on prescription drug spending and having diagnoses of dyslipidemia and myocardial infarction werea ssociated with al ower total gap in the Tobit model. We did not find similar relationships with the odds of being nonpersistent and the risk of having an unallowable gap in the logistic regression and Cox proportional hazards models. These differences in independent predictors between the Tobit model compared with the logistic regression and the Cox proportional hazards model may be due to the fact that the Tobit model allows for persistence (total gap) as ac ontinuous variable, while the logistic regression requires persistence to be dichotomized (persistent vs. nonpersistent) and persistence is measured as time to an unallowable gap or duration in the Cox proportional hazards model.
We adapted Andersen' sb ehavioral model of health services use as ac onceptual framework to select important variables to control in examining the relationship between cost-sharing and medication persistence. The results suggested that Andersen' sm odel is valid as ag uidance to select predictor variables for examining medication persistence. In this study,for example, the logistic model explained approximately 9% of the variance in medication refill persistence (pseudo-R 2 =0.09). Our R 2 value is improved over that of Cole et al., who reported an R 2 value of 0.06. 23

Limitations
The primaryl imitation of this study is its cross-sectional design, which is vulnerable to the effects of confounding factors. The 9% pseudo-R 2 value in our logistic regression model suggests that asubstantial portion of the variance in medication refill persistence was not explained by our model, ap roblem typical of cross-sectional studies of this topic. Previous observational work has indicated that patients initiating treatments with generic drugs (lower cost-share) have somewhat higher adherence rates than do those initiating with brand drugs (higher cost-share); however,ar andomized study is necessaryf or a rigorous test of the effects of initial cost-shareonearly medication persistence. 26 The need for further research is highlighted by recent quasi-experimental (pre-post with comparison) study of diabetic supply utilization beforeand after the implementation of apolicy mandating provision of free diabetes supplies including glucose testing strips to patients with diabetes mellitus. Crosssectional analysis documented an association between higher cost-sharing levels for the testing strips and lower compliance with blood glucose testing guidelines prior to implementation. Yetimplementation of the free test strip policy was not associated with achange in adherence to testing guidelines, even among lower-income patients and those paying the highest cost-share prior to the policy change. 50 Second, medication persistence is defined narrowly in the present study to include single-agent ACEI or ARB. While switching between single-agent ARB or ACEI was permitted, drug therapy was considered terminated if the patient switched to an ACEI or ARB in combination with hydrochlorothiazide (HCTZ) or to an antihypertensive in ad ifferent class such as ac alcium channel blocker,d iuretic, or ab eta blocker.T hird, our measurements of refill persistence depended on days supply recorded in pharmacy claims data. ACEI or ARB refill persistence may be underestimated in this study because other sources for acquiring prescription medications, such as free samples from physicians, could not be identified in claims data.
Fourth, the subjects of this study may have self-selected the Midwest commercial insurer as their health plan. Although pharmacy benefits areusually the same within one health plan and similar across different health plans for the same employer,this study may have been subject to aselection bias. However,toour knowledge, the pharmacy benefits werethe same regardless of the health benefits selected by the member within one employer.
Fifth, the members of this study werem ostly younger than 65 years. Therefore, the results of this study may not be generalizable to older adults.
Sixth, our results arelimited to members newly initiating angiotensin system-blocking agents and may not be generalizable to established medication users or other drug classes. Seventh, we attributed interruption of refills to members' nonpersistence behavior.However,these interruption decisions may have been made by physicians as ar esult of ineffectiveness or side effects. Nonetheless, these decisions should affect members with lower and higher levels of cost-sharing equally.E ighth, some control variables, including income and race, werem easured on an aggregate Zip Code level instead of on the individual level. Ninth, the duration of this study may be of concernt os ome readers. We followed the members for aminimum of 6months and up to 1year.The relatively short study duration was based on previous research, which has shown that the largest decrease in antihypertensive persistence occurs between 3and 6months after initiating therapy. 40,51 Finally,i n2 004, benazepril (Lotensin) and quinapril (Accupril) became generically available in Februarya nd December,respectively,resulting in lower member cost-sharing (i.e., generic cost-sharing). These 2drugs wereused by less than 5% of ACEI users and exclusion of these members in sensitivity analyses did not influence the results.

Policy Implication
This study has several implications for policy making. Payers have experimented with lowering medication cost-sharing for chronic diseases such as hypertension, hyperlipidemia, and diabetes, wheremedication has been shown to prevent morbidity and mortality. 52,53 Although zero-dollar member cost-sharing for selected chronic conditions has been proposed, as tarting point may be az ero-dollar or near zero-dollar cost-sharing for generic drugs, which has been adopted by some employers. 54 A zero-dollar generic cost-sharew ill potentially reduce cost to all beneficiaries and improve persistence; however,t oo ur knowledge, currently therea re no well-controlled studies indicating that zero-dollar cost-sharing improves medication adherence. Knowing arelationship exists between how much an individual pays for medication and how long he or she will remain persistent is the first step to improving pharmacy benefits designs. We echo the statements made by others: "The challenge remains to make individuals moresensitive to the cost of treatment without encouraging them to forgo cost effective care." 52

nn CONCLUSION
This study adds to the literaturet hrough further quantifying the association between the amount of member prescription cost-sharea nd medication refill persistence. Among members newly initiating an ACEI or ARB, a$ 10 greater cost-sharew as associated with 31.9% greater odds of being nonpersistent at 6 months after initiating therapy. To our knowledge, this is the first study to quantify the association between the dollar amount of member cost-share and total gap in therapy among members newly initiating ACEI or ARB therapy.F or every$ 10 greater cost-share, we found an associated 18.9% increase in total medication gap during the first 6 months of follow-up. Further research is needed to validate these findings and to investigate this relationship among other antihypertensive drug classes and other chronic medications. Insurers should consider the impact that cost-share has on angiotensin system-blocking medication persistence when designing their pharmacy benefit offerings.